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CN107375284A - The detection of cold menthol receptor TRPM8 low molecule amount conditioning agent and purposes - Google Patents

The detection of cold menthol receptor TRPM8 low molecule amount conditioning agent and purposes Download PDF

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Publication number
CN107375284A
CN107375284A CN201710396933.0A CN201710396933A CN107375284A CN 107375284 A CN107375284 A CN 107375284A CN 201710396933 A CN201710396933 A CN 201710396933A CN 107375284 A CN107375284 A CN 107375284A
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Prior art keywords
leu
composition
trpm8
val
glu
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CN201710396933.0A
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CN107375284B (en
Inventor
T·萨布科夫斯基
C·博尔施韦勒
J·维特恩伯格
M·克龙
H·青克
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BASF SE
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BASF SE
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Abstract

The present invention relates to the detection of cold menthol receptor TRPM8 low molecule amount conditioning agent and purposes.Specifically, the present invention relates to cold menthol receptor TRPM8 new conditioning agent, the method that TRPM8 acceptors are adjusted using these conditioning agents；The conditioning agent is used for the purposes for inducing cold sensation；And the article and instrument prepared using these conditioning agents.

Description

The detection of cold menthol receptor TRPM8 low molecule amount conditioning agent and purposes
The application is the divisional application for the Chinese invention patent application 201410336374.0 submitted on July 15th, 2014, Described Chinese invention patent application 201410336374.0 be August in 2009 submit within 26th, entitled " cold peppermint The PCT application PCT/EP2009/061019 of the detection of alcohol acceptor TRPM8 low molecule amount conditioning agent and purposes " division Shen Please, the date that the PCT application enters National Phase in China is on 2 28th, 2011, Application No. 200980133390.7.
Technical field
The present invention relates to cold menthol receptor TRPM8 New Regulator, and TRPM8 acceptors are adjusted using these conditioning agents Method；The purposes of the conditioning agent induction cold sensation；And the article and composition prepared using these conditioning agents.
Background technology
Cold menthol receptor TRPM8 (also referred to as freezing mask acceptor (CMR) 1) belongs to " transient receptor potential ion passage " family Race, expressed in a kind of specific neuron, hole is formed in cell membrane, and (4 units combine to form four in all cases Aggressiveness), its selective permission Ca2+Ion passes through.The albumen has 6 membrane spaning domains and kytoplasm C and N-terminal.It is low Warm (preferably 10-25 DEG C) can stimulate this receptor, produce signal transduction, and the signal is interpreted as cold sensation by nervous system.Should be by Body was described as cold receptors in more publications in 2002 and (Peier AM etc., feels cold stimulation and menthol first TRP passages, 2002Mar 8；108(5):705-15；McKemy DD etc., the identification of cold acceptor disclose TRP passages in heat Generally effect in sensation, Nature.2002Mar 7； 416(6876):52-8；Zuker CS. Neurobiologys：Cold ion Passage, Nature.2002 Mar 7；416(6876):27-8).
The compound of refrigeration, such as menthol, there is important work in flavor enhancement and fragrance industry since some time With to produce fresh and clean feel combination.For compound menthol, show it as the natural of acceptor TRPM8 Conditioning agent works (McKemy D.D., Molecular Pain1,2005,16；McKemy D.D.,Nature416, 2002,52-58；Peier A.M.,Cell108,2002,705-715；Dhaka A.,Annu.Rev.Neurosci.29, 2006,135-161).By using menthol, activating TRPM8 so that Ca2+Flow into cold sensitive neuron.Caused electric signal Finally it is perceived as cold sensation.Menthol concentration rise can cause to stimulate and anaesthetic effect.In addition, many publications describe Menthol derivative (BP 1971#1315761 with similar effect； Watson H.R., J.Soc.Cosmet.Chem.29,1978,185-200；Furrer S.M.,Chem. Percept.1,2008,119-126)。 Significant TRPM8 mediating effect+6s, such as Icilin are also generated also in structure with the incoherent individual compound of menthol (Wei E.T.,J.Pharm.Pharmacol. 35,1983,110-112；WO 2004/026840), WS-23 or patent application Listed compound in WO 2007/019719.
Another effect of the material of regulation TRPM8 acceptors and/or the analog in its insect is that the expeling to insect is made With (WO 2002/015692；WO 2004/000023, US 2004/0028714), its antineoplaston (such as influence before Row adenoncus knurl), it is also active in inflammatory pain/hyperalgesic treatment, and can be used as TRPM8 antagonists effectively to control Treat bladder syndrome or bladder hyperactivity (Beck B.Cell Calcium,41,2007,285-294；Levine J.D.Biochim.Biophys. Acta,Mol.Basis Dis.1772,2007,989-1003；Mukerji G.,BMC Urology 6, 2006,6；US 2003/0207904；US 2005/6893626,Dissertation Behrendt H.J. 2004,Bochum；Lashinger E.S.R.Am.J.Physiol.Renal Physiol. Am J Physiol Renal Physiol.2008Jun 18. [electronic edition before publication]；PMID: 18562636).
However, TRPM8 conditioning agents many so far are in effect intensity, duration of effect, skin/mucosal irritation, gas Still there is defect in terms of taste, the sense of taste, dissolubility and/or volatility.
The content of the invention
Therefore, it is an object of the invention to identify the novel substance of regulation TRPM8 acceptors, it can be used as hitherto known The alternatives of conditioning agent.These compounds should also be particularly suitable for use in cosmetics (such as hair care, skin care, oral care), nutrition Product (feed/food), textile, OTC products (such as burn ointment), medicine (such as oncotherapy, bladder weakness), packaging Field is used as insecticide or pest repellant.
Detailed description of the invention:
1. generic term defines：
In the literature, " TRPM8 " has multiple synonyms：TRPP8, LTRPC6, CMR1, MGC2849, transient receptor potential Cationic channel subfamily M member 8.In the background of the invention, all titles are covered.All features of this receptor are repaiied In decorations are also included within, e.g. particularly splice variant, hypotype, such as TRPM8CRA_a, TRPM8CRA_b, and from various lifes All similar acceptors in object such as people, mouse, rat.The nucleotides of isoacceptor and amino acid sequence are not known per se , listed in sequence library.Thus, for example hTRPM8 sequence information can be represented with accession number NM_024080.
In present disclosure, " conditioning agent " refer to can in vivo and/or in vitro as TRPM8 receptor stimulating agents and/ Or the compound that antagonist works.
Appropriate conditioning agent only can work as antagonist or activator herein, or simultaneously as antagonist and Activator works, and now, produces the concentration of stirring effect or antagonistic effect depending on the specific conditioning agent of selection.
Herein, " activator " refers to mediate TRPM8 receptor activations, thus induces Ca2+Into cold sensitive neuron, from And mediate the compound of cold sensation.On the contrary, " antagonist " refers to the compound for hindering TRPM8 receptor activations.
The mediators of the present invention can be sent out by reversible or irreversible, specific or non-specific binding TRPM8 acceptor molecules Wave its effect.Generally, and acceptor molecule combination by such as hydrophobic effect ionically and/or non-ionically and non-covalent Occur.Herein, it is " specific " to include and one or more different TRPM8 acceptor molecules (such as separate sources or not With the TRPM8 molecules of hypotype) exclusive interaction.On the contrary, " nonspecific " refers to the conditioning agent and a variety of differences The acceptor molecule of function and/or sequence interacts, but can produce to the receptor agonism and/or antagonism desired by TRPM8 Regulation is (as described above).
2. preferred embodiment
Present invention firstly relates to method that is external or adjusting cold menthol receptor TRMP8 in vivo, especially people TRPM8 by Body, wherein the acceptor contacts with least one compound selected from polycyclic organic compound, the compound is using restructuring In the cytoactive test that the cell of expression people's TRPM8 acceptors is carried out, these cells pair are particularly have adjusted at the standard conditions Ca2+The permeability of ion.
In the portion, " standard conditions " are understood to mean that the reality carried out using the HEK293 cells through people TRPM8 conversions Test, the cell is loaded with calcium sensitive dye (such as Fluo-4AM, i.e., fluoro- 4- acetoxy-methyl esters) and adds test chemical combination afterwards Thing, and color change is detected, experimentation is carried out at 37 DEG C, described in following article embodiment 3, or referring to Behrendt etc. (2004), see above).
Particularly, the modulating compound includes at least two 4- to 7- yuan of rings, its be each independently carbocyclic ring or heterocycle, It is monocyclic or polycyclic, wherein at least two can be condensed optionally or screw connection in these rings.Other of suitable ring connection are unrestricted Property example include chemical single bond between ring carbon atom and/or ring hetero atom, connected by 2-6 member carbon bridged group, wherein each Carbon atom can be replaced by such as N, O or S hetero atom.In addition, the ring and bridging group can optionally carry substituent, it is described to take Dai Ji is selected from ketone group ,-OH ,-SH ,-CN ,-NO2、-C1-6- alkyl or C2-4- alkenyl, wherein in alkyl or alkenyl, one Individual or multiple H atoms can be replaced by such as F, Cl, Br or I halogen.
Carbocyclic ring herein includes 4,5,6 or 7 carbon atoms；In addition to ring carbon atom, it is identical or not that heterocycle includes 1-3 Same ring hetero atom, such as O, N and S atom.Ring herein can be saturation, single or multiple unsaturation independently of one another , such as aromatic ring.
The conditioning agent that the present invention uses is for cell Ca2+Permeability has excitement or antagonistic effect.Specifically, it is described Conditioning agent is at least one formula 1-19 in table 1 below compound.
Table 1：According to the conditioning agent of the present invention
Wherein compound can the pure or enriched form of chemistry exist, be that single stereoisomer or stereoisomer mix Thing form.In addition, the compound can be uncharged or its salt form, such as acid-addition salts.Functional group can optionally by etc. The chemical group of valency is replaced；Fluorine atom can be replaced by other halogen atoms, such as Cl, Br or I；Oxygen atom (such as ether) can Replaced by corresponding methylthio group, vice versa；Ketone groups can be replaced by corresponding sulfinyl.The chemical combination being described in detail above Thing is chemical substance known per se, commercially available or obtained by conventional methodology of organic synthesis.
Thus, for example following compounds are known：
Compound 1, No. CAS:99602-94-5 (3R- is cis)
Compound 2, No. CAS:165753-08-2
Compound 3, No. CAS:338771-57-6
Compound 4, No. CAS:878942-21-3
Compound 5, No. CAS:748783-13-3
If modified forms or derivative also show the biological activity (acceptor TRPM8 regulation) needed, then it And functional analogue or function equivalence compound.
In addition, present invention additionally comprises the derivative for making specifically disclosed material be coupled with solid phase carrier；People in the art Corresponding joint/the spacer group of choosing multiple known to member.The derivatization can be carried out before solid phase is coupled to, or only by Coupling produces.
The invention further relates to TRPM8 receptor modulators, especially activator to induce the cold sensation of people and/or animal, especially It is local, i.e., the purposes in the cold sensation of skin or oral cavity, wherein the conditioning agent is as hereinbefore defined.Work as compound When showing the stirring effect for hTRPM8 in the test of above-mentioned cytoactive, it is referred to as " induction cold sensation ".
The invention further relates to purposes of the TRPM8 receptor modulators as the active component of pharmaceutical composition, wherein the tune Save agent as hereinbefore defined.
The invention further relates to TRPM8 receptor modulators in prostate cancer therapy, the weak treatment of bladder or pain therapy Purposes, wherein the conditioning agent is as hereinbefore defined.
The invention further relates to purposes of the TRPM8 receptor modulators as insect repellent or insecticide, wherein the regulation Agent is as hereinbefore defined.
The invention further relates to TRPM8 receptor modulators in induction to a variety of form processings (such as fiber, fabric, mould Modeling) packaging (such as being made up of paper or plastics) cold sensation in purposes, wherein particularly when contacting packaging material, it is cold Feel to become notable, wherein the conditioning agent is as hereinbefore defined.In the contents of the section, the material can pass through a variety of ways Footpath is combined with packaging material：Such as by spin coating, gravure, micro-encapsulated form, be introduced directly into packaging material (example Such as extruding), the covalent coupling of the appropriate derivative of conditioning agent (molecule and bag are helped by appropriate sept/linking group Package material is reversible or irreversibly combines).Suitable method known to those skilled in the art.
The invention further relates to purposes of the TRPM8 receptor modulators in the cold sensation of induction textile, wherein the regulation Agent is as hereinbefore defined.In the contents of the section, the material can be combined by number of ways with textile：Such as pass through Spin coating, gravure, micro-encapsulated form, (such as extruding), the appropriate derivative of conditioning agent are introduced directly into textile material Covalent coupling (help molecule and textile material reversible by appropriate sept/linking group or irreversibly tie Close).Suitable method known to those skilled in the art.
The invention further relates to according to the material defined above purposes as TRPM8 receptor modulators in itself, especially make For activator and/or antagonist.
The invention further relates to the composition for including at least one compound defined above.Particularly, the composition choosing From：
A) pharmaceutical composition, such as anti-tumor compositions, the composition of bladder disease, anodyne are treated；
B) food, such as ice cream, mousse, missible oil, beverage, cake.
C) oral care composition, such as toothpaste, mouthwash, chewing gum, flavorants.
D) skin care or Haircare composition, such as suncream, sunburn cream, lotion, shampoo, plaster, collutory, washing lotion, shave Mao Shuan, conditioning agent, mildy wash, soap, bath oil and bath foam, antiperspirant, deodorant.
E) pest repellant, insecticide.
In addition to the conventional ingredient of various concrete compositions, the composition includes at least one present invention of effective dose Conditioning agent.In the contents of the section, " effective " concentration for representing the conditioning agent is enough the effect for bringing needs, such as medicine Pharmacological effect or sensory effect, such as cold smell effect after the application composition (example is as applied to skin).
Optionally, according to the present invention compound can with other known active ingredient combinations, especially those there is phase With effect.For example, can be combined with known refrigerant compounds, such as menthol, menthones, N- ethyl-p-menthan formyls Amine (WS-3), N-2,3- trimethyl -2- butanamides (WS-23), menthyl lactate (ML), peppermint Ketone glycerine acetal (MGA), monomenthyl succinateMonomenthyl glutarate, O- are thin Lotus base glycerol, N, N- dimethyl succinate acid amides menthyl esters.
The invention further relates to textile, such as shirt, trousers, socks, towel, and it uses at least one defined above Compound arranges (finish) (especially on the surface).
The invention further relates to the packaging material combined with least one compound defined above.
The present invention is described referring now to following nonrestrictive working Examples.
Brief description of the drawings
Fig. 1 is shown from according to sequence library accession numberNM_024080HTRPM8 acceptors (a) mRNA sequence Amino acid sequence (b).
Fig. 2 shows coding hTRPM8 plasmid pInd_M8 Vector map, and it has been used for transfected HEK 293.
Embodiment
Experimental section:
1-people of embodiment TRPM8 clone
The starting point of people's TRPM8 receptor clonings is LnCaP cDNA libraries.It is for example commercially available (such as BioChain, Hayward, USA) or use human prostate cancer cell line LnCaP (example of the standard reagent box from Androgen-sensitive Such as ATCC, CRL1740 or ECACC, 89110211) prepare.
Standard method PCR amplifications and clones coding TRPM8 sequence can be used (referring to Fig. 1 a；And http:// www.ncbi.nlm.nih.gov/entrez/viewer.fcgiDb=nuccore＆id=10968969 4).By this People's TRPM8 genes of method separation be used to prepare plasmid pInd_M8, and it is constructed by Fig. 2 plasmid map and illustrated.
Or TRPM8 genes also can be by synthetically prepared.
The passage of embodiment 2-HEK293 test cells
The HEK293 cell lines for preparing stable transfection people TRPM8DNA (referring to above-mentioned plasmid pInd-M8) are thin as test Born of the same parents' system.Herein preferably by introducing into plasmid offer with tetracycline induction TRPM8 expression HEK293.
The method of the appropriate test cell system of production known to those skilled in the art.For example, the cell that the present invention uses Preparation details referring to Behrendt H.J. etc., Br.J.Pharmacol.141,2004,737-745 or Behrendt opinion Text " Vergleichende funktionale Untersuchungen des Hitze-Capsaicin-Rezeptors (TRPV1)und des -Menthol-Rezeptors (TRPM8)in rekombinanten und nativen [hot capsaicin receptor (TRPV1) and cold menthol receptor (TRPM8) are in restructuring and n cell system by Zellsystemen " In function comparative studies], referring to：
http://www-brs.ub.ruhr-uni-bochum.de/netahtml/HSS/Diss/Behrendt HansJoerg/diss.pdf。
Especially quote these document disclosures.
The measure of embodiment 3-TRPM8 conditioning agents
Using the suitable experiment of the experiment with being described in document, referring to Behrendt H.J. et al., Br.J.Pharmacol.141,2004,737-745.The excitement of acceptor or antagonism pass through Ca2+Sensitive dyes (such as FURA, Fluo-4 etc.) quantify.According to its own feature, activator makes Ca2+Signal increase, antagonist is for example in the presence of menthol Make Ca2+Signal is reduced (to be detected, it has by Ca each via dyestuff Fluo-42+Caused different photoluminescent property).
A) test method：
First, the fresh medium of the HEK cells of conversion is prepared in a manner known per se in Tissue Culture Flask.Make Test cell HEK293-TRPM8 is separated from Tissue Culture Flask with trypsase, by every cell of 100 μ l culture mediums 40 000/ Hole is seeded in 96 orifice plates (the poly- D-Lys-coatings of Greiner#655948).For inducing receptor TRPM8, to grown cultures Tetracycline is added in base, and (DMEM/HG, 10% without tetracycline FCS, 4mM Glus, 15 μ g/ml blasticidins, 100 μ g/ Ml hygromycin Bs, 1 μ g/ml tetracyclines).Second day, cell loading Fluo-4AM dyestuffs, tested.Use the following steps：
- in every 100 μ l culture mediums, (DMEM/HG, 10% without tetracycline FCS, 4mM Glus, 15 μ g/ml sterilizings Element, 100 μ g/ml hygromycin Bs, 1 μ g/ml tetracyclines) in each add 100 μ l/ holes dye solution Ca-4kit (RB 141, Molecular Devices)。
- 30 minutes/37 DEG C/5%CO is incubated in incubator2, 30 minutes/RT.
- prepare for examination material (in 200 μ l HBSS buffer solutions, various concentrations) and positive control (various concentrations it is thin Lotus alcohol, icilin and ionomycin, in 200 μ l HBSS buffer solutions) and negative control (only 200 μ l HBSS buffer solutions).
- substances are added with the amount in 50 μ l/ holes, excite in 485nm, the change of 520nm transmitting measure fluorescence (such as Determining instrument FLIPR, Molecular Devices or NovoStar, BMG), the effect of evaluation different material/concentration, it is determined that EC50 values.
Substances are measured for 0.1-200 μM in triplicate with concentration.Compound is generally stored in DMSO solution In, it is diluted to maximum DMSO concentration 2% and is measured.
B) result of the test
The EC50 values of conditioning agent measure of the present invention are summarized in table 2 below.
Table 2:Activity of the substances for people's acceptor TRPM8
The evaluation it has surprisingly been found that first can preparation structure be markedly different from known TRPM8 receptor agonisms Agent, such as (-) menthol, icilin and other Behrendt H.J. etc. are in Br.J. Pharmacol.141,2004,737- The TRPM8 receptor stimulating agents of activator described in 745 (referring to tables 1), also, it has than (-) peppermint in some cases Alcohol is preferably active, or suitable with icilin effects.
The preparation of 4-collutory of embodiment
Prepare the collutory of following composition：
To prepare collutory, mentioned component is mixed with the amount.
Herein with particular reference to the disclosure of cited document resource.
Sequence table
<110>BASF European Co., Ltd
<120>The detection of cold menthol receptor TRPM8 low molecule amount conditioning agent and purposes
<130> M/49197-PCT
<160> 2
<170>PatentIn version 3s .3
<210> 1
<211> 5621
<212> DNA
<213>People
<400> 1
aagaaaatcc tgcttgacaa aaaccgtcac ttaggaaaag atgtcctttc gggcagccag 60
gctcagcatg aggaacagaa ggaatgacac tctggacagc acccggaccc tgtactccag 120
cgcgtctcgg agcacagact tgtcttacag tgaaagcgac ttggtgaatt ttattcaagc 180
aaattttaag aaacgagaat gtgtcttctt taccaaagat tccaaggcca cggagaatgt 240
gtgcaagtgt ggctatgccc agagccagca catggaaggc acccagatca accaaagtga 300
gaaatggaac tacaagaaac acaccaagga atttcctacc gacgcctttg gggatattca 360
gtttgagaca ctggggaaga aagggaagta tatacgtctg tcctgcgaca cggacgcgga 420
aatcctttac gagctgctga cccagcactg gcacctgaaa acacccaacc tggtcatttc 480
tgtgaccggg ggcgccaaga acttcgccct gaagccgcgc atgcgcaaga tcttcagccg 540
gctcatctac atcgcgcagt ccaaaggtgc ttggattctc acgggaggca cccattatgg 600
cctgatgaag tacatcgggg aggtggtgag agataacacc atcagcagga gttcagagga 660
gaatattgtg gccattggca tagcagcttg gggcatggtc tccaaccggg acaccctcat 720
caggaattgc gatgctgagg gctatttttt agcccagtac cttatggatg acttcacaag 780
agatccactg tatatcctgg acaacaacca cacacatttg ctgctcgtgg acaatggctg 840
tcatggacat cccactgtcg aagcaaagct ccggaatcag ctagagaagt atatctctga 900
gcgcactatt caagattcca actatggtgg caagatcccc attgtgtgtt ttgcccaagg 960
aggtggaaaa gagactttga aagccatcaa tacctccatc aaaaataaaa ttccttgtgt 1020
ggtggtggaa ggctcgggcc agatcgctga tgtgatcgct agcctggtgg aggtggagga 1080
tgccctgaca tcttctgccg tcaaggagaa gctggtgcgc tttttacccc gcacggtgtc 1140
ccggctgcct gaggaggaga ctgagagttg gatcaaatgg ctcaaagaaa ttctcgaatg 1200
ttctcaccta ttaacagtta ttaaaatgga agaagctggg gatgaaattg tgagcaatgc 1260
catctcctac gctctataca aagccttcag caccagtgag caagacaagg ataactggaa 1320
tgggcagctg aagcttctgc tggagtggaa ccagctggac ttagccaatg atgagatttt 1380
caccaatgac cgccgatggg agtctgctga ccttcaagaa gtcatgttta cggctctcat 1440
aaaggacaga cccaagtttg tccgcctctt tctggagaat ggcttgaacc tacggaagtt 1500
tctcacccat gatgtcctca ctgaactctt ctccaaccac ttcagcacgc ttgtgtaccg 1560
gaatctgcag atcgccaaga attcctataa tgatgccctc ctcacgtttg tctggaaact 1620
ggttgcgaac ttccgaagag gcttccggaa ggaagacaga aatggccggg acgagatgga 1680
catagaactc cacgacgtgt ctcctattac tcggcacccc ctgcaagctc tcttcatctg 1740
ggccattctt cagaataaga aggaactctc caaagtcatt tgggagcaga ccaggggctg 1800
cactctggca gccctgggag ccagcaagct tctgaagact ctggccaaag tgaagaacga 1860
catcaatgct gctggggagt ccgaggagct ggctaatgag tacgagaccc gggctgttga 1920
gctgttcact gagtgttaca gcagcgatga agacttggca gaacagctgc tggtctattc 1980
ctgtgaagct tggggtggaa gcaactgtct ggagctggcg gtggaggcca cagaccagca 2040
tttcatcgcc cagcctgggg tccagaattt tctttctaag caatggtatg gagagatttc 2100
ccgagacacc aagaactgga agattatcct gtgtctgttt attataccct tggtgggctg 2160
tggctttgta tcatttagga agaaacctgt cgacaagcac aagaagctgc tttggtacta 2220
tgtggcgttc ttcacctccc ccttcgtggt cttctcctgg aatgtggtct tctacatcgc 2280
cttcctcctg ctgtttgcct acgtgctgct catggatttc cattcggtgc cacacccccc 2340
cgagctggtc ctgtactcgc tggtctttgt cctcttctgt gatgaagtga gacagtggta 2400
cgtaaatggg gtgaattatt ttactgacct gtggaatgtg atggacacgc tggggctttt 2460
ttacttcata gcaggaattg tatttcggct ccactcttct aataaaagct ctttgtattc 2520
tggacgagtc attttctgtc tggactacat tattttcact ctaagattga tccacatttt 2580
tactgtaagc agaaacttag gacccaagat tataatgctg cagaggatgc tgatcgatgt 2640
gttcttcttc ctgttcctct ttgcggtgtg gatggtggcc tttggcgtgg ccaggcaagg 2700
gatccttagg cagaatgagc agcgctggag gtggatattc cgttcggtca tctacgagcc 2760
ctacctggcc atgttcggcc aggtgcccag tgacgtggat ggtaccacgt atgactttgc 2820
ccactgcacc ttcactggga atgagtccaa gccactgtgt gtggagctgg atgagcacaa 2880
cctgccccgg ttccccgagt ggatcaccat ccccctggtg tgcatctaca tgttatccac 2940
caacatcctg ctggtcaacc tgctggtcgc catgtttggc tacacggtgg gcaccgtcca 3000
ggagaacaat gaccaggtct ggaagttcca gaggtacttc ctggtgcagg agtactgcag 3060
ccgcctcaat atccccttcc ccttcatcgt cttcgcttac ttctacatgg tggtgaagaa 3120
gtgcttcaag tgttgctgca aggagaaaaa catggagtct tctgtctgct gtttcaaaaa 3180
tgaagacaat gagactctgg catgggaggg tgtcatgaag gaaaactacc ttgtcaagat 3240
caacacaaaa gccaacgaca cctcagagga aatgaggcat cgatttagac aactggatac 3300
aaagcttaat gatctcaagg gtcttctgaa agagattgct aataaaatca aataaaactg 3360
tatgaactct aatggagaaa aatctaatta tagcaagatc atattaagga atgctgatga 3420
acaattttgc tatcgactac taaatgagag attttcagac ccctgggtac atggtggatg 3480
attttaaatc accctagtgt gctgagacct tgagaataaa gtgtgtgatt ggtttcatac 3540
ttgaagacgg atataaagga agaatatttc ctttatgtgt ttctccagaa tggtgcctgt 3600
ttctctctgt gtctcaatgc ctgggactgg aggttgatag tttaagtgtg ttcttaccgc 3660
ctcctttttc ctttaatctt atttttgatg aacacatata taggagaaca tctatcctat 3720
gaataagaac ctggtcatgc tttactcctg tattgttatt ttgttcattt ccaattgatt 3780
ctctactttt cccttttttg tattatgtga ctaattagtt ggcatattgt taaaagtctc 3840
tcaaattagg ccagattcta aaacatgctg cagcaagagg accccgctct cttcaggaaa 3900
agtgttttca tttctcagga tgcttcttac ctgtcagagg aggtgacaag gcagtctctt 3960
gctctcttgg actcaccagg ctcctattga aggaaccacc cccattccta aatatgtgaa 4020
aagtcgccca aaatgcaacc ttgaaaggca ctactgactt tgttcttatt ggatactcct 4080
cttattattt ttccattaaa aataatagct ggctattata gaaaatttag accatacaga 4140
gatgtagaaa gaacataaat tgtccccatt accttaaggt aatcactgct aacaatttct 4200
ggatggtttt tcaagtctat tttttttcta tgtatgtctc aattctcttt caaaatttta 4260
cagaatgtta tcatactaca tatatacttt ttatgtaagc tttttcactt agtattttat 4320
caaatatgtt tttattatat tcatagcctt cttaaacatt atatcaataa ttgcataata 4380
ggcaacctct agcgattacc ataattttgc tcattgaagg ctatctccag ttgatcattg 4440
ggatgagcat ctttgtgcat gaatcctatt gctgtatttg ggaaaatttt ccaaggttag 4500
attccaataa atatctattt attattaaat attaaaatat ctatttatta ttaaaaccat 4560
ttataaggct ttttcataaa tgtatagcaa ataggaatta ttaacttgag cataagatat 4620
gagatacatg aacctgaact attaaaataa aatattatat ttaaccctta gtttaagaag 4680
aagtcaatat gcttatttaa atattatgga tggtgggcag atcacttgag gtcaggagtt 4740
cgagaccagc ctggccaaca tggcaaaacc acatctctac taaaaataaa aaaattagct 4800
gggtgtggtg gtgcactcct gtaatcccag ctactcagaa ggctgaggta caagaattgc 4860
tggaacctgg gaggcggagg ttgcagtgaa ccaagattgc accactgcac tccagccggg 4920
gtgacagagt gagactccga ctgaaaataa ataaataaat aaataaataa ataaataaat 4980
attatggatg gtgaagggaa tggtatagaa ttggagagat tatcttactg aacacctgta 5040
gtcccagctt tctctggaag tggtcgtatt tgagcaggat gtgcacaagg caattgaaat 5100
gcccataatt agtttctcag ctttgaatac actataaact cactggctga aggaggaaat 5160
tttagaagga agctactaaa agatctaatt tgaaaaacta caaaagcatt aactaaaaaa 5220
gtttattttc cttttgtctg ggcagtagtg aaaataacta ctcacaacat tcactatgtt 5280
tgcaaggaat taacacaaat aaaagatgcc tttttactta aacaccaaga cagaaaactt 5340
gcccaatact gagaagcaac ttgcattaga gagggaactg ttaaatgttt tcaacccagt 5400
tcatctggtg gatgtttttg caggttactc tgagaatttt gcttatgaaa aatcattatt 5460
tttagtgtag ttcacaataa tgtattgaac atacttctaa tcaaaggtgc tatgtccttg 5520
tgtatggtac taaatgtgtc ctgtgtactt ttgcacaact gagaatcctg cagcttggtt 5580
taatgagtgt gttcatgaaa taaataatgg aggaattgtc a 5621
<210> 2
<211> 1104
<212> PRT
<213>People
<400> 2
Met Ser Phe Arg Ala Ala Arg Leu Ser Met Arg Asn Arg Arg Asn Asp
1 5 10 15
Thr Leu Asp Ser Thr Arg Thr Leu Tyr Ser Ser Ala Ser Arg Ser Thr
20 25 30
Asp Leu Ser Tyr Ser Glu Ser Asp Leu Val Asn Phe Ile Gln Ala Asn
35 40 45
Phe Lys Lys Arg Glu Cys Val Phe Phe Thr Lys Asp Ser Lys Ala Thr
50 55 60
Glu Asn Val Cys Lys Cys Gly Tyr Ala Gln Ser Gln His Met Glu Gly
65 70 75 80
Thr Gln Ile Asn Gln Ser Glu Lys Trp Asn Tyr Lys Lys His Thr Lys
85 90 95
Glu Phe Pro Thr Asp Ala Phe Gly Asp Ile Gln Phe Glu Thr Leu Gly
100 105 110
Lys Lys Gly Lys Tyr Ile Arg Leu Ser Cys Asp Thr Asp Ala Glu Ile
115 120 125
Leu Tyr Glu Leu Leu Thr Gln His Trp His Leu Lys Thr Pro Asn Leu
130 135 140
Val Ile Ser Val Thr Gly Gly Ala Lys Asn Phe Ala Leu Lys Pro Arg
145 150 155 160
Met Arg Lys Ile Phe Ser Arg Leu Ile Tyr Ile Ala Gln Ser Lys Gly
165 170 175
Ala Trp Ile Leu Thr Gly Gly Thr His Tyr Gly Leu Met Lys Tyr Ile
180 185 190
Gly Glu Val Val Arg Asp Asn Thr Ile Ser Arg Ser Ser Glu Glu Asn
195 200 205
Ile Val Ala Ile Gly Ile Ala Ala Trp Gly Met Val Ser Asn Arg Asp
210 215 220
Thr Leu Ile Arg Asn Cys Asp Ala Glu Gly Tyr Phe Leu Ala Gln Tyr
225 230 235 240
Leu Met Asp Asp Phe Thr Arg Asp Pro Leu Tyr Ile Leu Asp Asn Asn
245 250 255
His Thr His Leu Leu Leu Val Asp Asn Gly Cys His Gly His Pro Thr
260 265 270
Val Glu Ala Lys Leu Arg Asn Gln Leu Glu Lys Tyr Ile Ser Glu Arg
275 280 285
Thr Ile Gln Asp Ser Asn Tyr Gly Gly Lys Ile Pro Ile Val Cys Phe
290 295 300
Ala Gln Gly Gly Gly Lys Glu Thr Leu Lys Ala Ile Asn Thr Ser Ile
305 310 315 320
Lys Asn Lys Ile Pro Cys Val Val Val Glu Gly Ser Gly Gln Ile Ala
325 330 335
Asp Val Ile Ala Ser Leu Val Glu Val Glu Asp Ala Leu Thr Ser Ser
340 345 350
Ala Val Lys Glu Lys Leu Val Arg Phe Leu Pro Arg Thr Val Ser Arg
355 360 365
Leu Pro Glu Glu Glu Thr Glu Ser Trp Ile Lys Trp Leu Lys Glu Ile
370 375 380
Leu Glu Cys Ser His Leu Leu Thr Val Ile Lys Met Glu Glu Ala Gly
385 390 395 400
Asp Glu Ile Val Ser Asn Ala Ile Ser Tyr Ala Leu Tyr Lys Ala Phe
405 410 415
Ser Thr Ser Glu Gln Asp Lys Asp Asn Trp Asn Gly Gln Leu Lys Leu
420 425 430
Leu Leu Glu Trp Asn Gln Leu Asp Leu Ala Asn Asp Glu Ile Phe Thr
435 440 445
Asn Asp Arg Arg Trp Glu Ser Ala Asp Leu Gln Glu Val Met Phe Thr
450 455 460
Ala Leu Ile Lys Asp Arg Pro Lys Phe Val Arg Leu Phe Leu Glu Asn
465 470 475 480
Gly Leu Asn Leu Arg Lys Phe Leu Thr His Asp Val Leu Thr Glu Leu
485 490 495
Phe Ser Asn His Phe Ser Thr Leu Val Tyr Arg Asn Leu Gln Ile Ala
500 505 510
Lys Asn Ser Tyr Asn Asp Ala Leu Leu Thr Phe Val Trp Lys Leu Val
515 520 525
Ala Asn Phe Arg Arg Gly Phe Arg Lys Glu Asp Arg Asn Gly Arg Asp
530 535 540
Glu Met Asp Ile Glu Leu His Asp Val Ser Pro Ile Thr Arg His Pro
545 550 555 560
Leu Gln Ala Leu Phe Ile Trp Ala Ile Leu Gln Asn Lys Lys Glu Leu
565 570 575
Ser Lys Val Ile Trp Glu Gln Thr Arg Gly Cys Thr Leu Ala Ala Leu
580 585 590
Gly Ala Ser Lys Leu Leu Lys Thr Leu Ala Lys Val Lys Asn Asp Ile
595 600 605
Asn Ala Ala Gly Glu Ser Glu Glu Leu Ala Asn Glu Tyr Glu Thr Arg
610 615 620
Ala Val Glu Leu Phe Thr Glu Cys Tyr Ser Ser Asp Glu Asp Leu Ala
625 630 635 640
Glu Gln Leu Leu Val Tyr Ser Cys Glu Ala Trp Gly Gly Ser Asn Cys
645 650 655
Leu Glu Leu Ala Val Glu Ala Thr Asp Gln His Phe Ile Ala Gln Pro
660 665 670
Gly Val Gln Asn Phe Leu Ser Lys Gln Trp Tyr Gly Glu Ile Ser Arg
675 680 685
Asp Thr Lys Asn Trp Lys Ile Ile Leu Cys Leu Phe Ile Ile Pro Leu
690 695 700
Val Gly Cys Gly Phe Val Ser Phe Arg Lys Lys Pro Val Asp Lys His
705 710 715 720
Lys Lys Leu Leu Trp Tyr Tyr Val Ala Phe Phe Thr Ser Pro Phe Val
725 730 735
Val Phe Ser Trp Asn Val Val Phe Tyr Ile Ala Phe Leu Leu Leu Phe
740 745 750
Ala Tyr Val Leu Leu Met Asp Phe His Ser Val Pro His Pro Pro Glu
755 760 765
Leu Val Leu Tyr Ser Leu Val Phe Val Leu Phe Cys Asp Glu Val Arg
770 775 780
Gln Trp Tyr Val Asn Gly Val Asn Tyr Phe Thr Asp Leu Trp Asn Val
785 790 795 800
Met Asp Thr Leu Gly Leu Phe Tyr Phe Ile Ala Gly Ile Val Phe Arg
805 810 815
Leu His Ser Ser Asn Lys Ser Ser Leu Tyr Ser Gly Arg Val Ile Phe
820 825 830
Cys Leu Asp Tyr Ile Ile Phe Thr Leu Arg Leu Ile His Ile Phe Thr
835 840 845
Val Ser Arg Asn Leu Gly Pro Lys Ile Ile Met Leu Gln Arg Met Leu
850 855 860
Ile Asp Val Phe Phe Phe Leu Phe Leu Phe Ala Val Trp Met Val Ala
865 870 875 880
Phe Gly Val Ala Arg Gln Gly Ile Leu Arg Gln Asn Glu Gln Arg Trp
885 890 895
Arg Trp Ile Phe Arg Ser Val Ile Tyr Glu Pro Tyr Leu Ala Met Phe
900 905 910
Gly Gln Val Pro Ser Asp Val Asp Gly Thr Thr Tyr Asp Phe Ala His
915 920 925
Cys Thr Phe Thr Gly Asn Glu Ser Lys Pro Leu Cys Val Glu Leu Asp
930 935 940
Glu His Asn Leu Pro Arg Phe Pro Glu Trp Ile Thr Ile Pro Leu Val
945 950 955 960
Cys Ile Tyr Met Leu Ser Thr Asn Ile Leu Leu Val Asn Leu Leu Val
965 970 975
Ala Met Phe Gly Tyr Thr Val Gly Thr Val Gln Glu Asn Asn Asp Gln
980 985 990
Val Trp Lys Phe Gln Arg Tyr Phe Leu Val Gln Glu Tyr Cys Ser Arg
995 1000 1005
Leu Asn Ile Pro Phe Pro Phe Ile Val Phe Ala Tyr Phe Tyr Met
1010 1015 1020
Val Val Lys Lys Cys Phe Lys Cys Cys Cys Lys Glu Lys Asn Met
1025 1030 1035
Glu Ser Ser Val Cys Cys Phe Lys Asn Glu Asp Asn Glu Thr Leu
1040 1045 1050
Ala Trp Glu Gly Val Met Lys Glu Asn Tyr Leu Val Lys Ile Asn
1055 1060 1065
Thr Lys Ala Asn Asp Thr Ser Glu Glu Met Arg His Arg Phe Arg
1070 1075 1080
Gln Leu Asp Thr Lys Leu Asn Asp Leu Lys Gly Leu Leu Lys Glu
1085 1090 1095
Ile Ala Asn Lys Ile Lys
1100

Claims (16)

1. cold menthol receptor TRMP8 method is adjusted in vitro, wherein the acceptor is selected from following compound with least one Contact, the compound have adjusted these in the cytoactive test carried out using the cell of recombination expression people's TRPM8 acceptors Cell is to Ca2+The permeability of ion：
2. the method as described in claim 1, wherein the conditioning agent is for cell Ca2+Ion permeability has excitement or antagonism Effect.
Purposes of the 3.TRPM8 receptor modulators in the composition of cold sensation of induction people and/or animal is prepared, wherein the tune Save agent as defined in claim 1.
4.TRPM8 receptor modulators are in the composition for prostate cancer therapy, the weak treatment of bladder or pain therapy is prepared Purposes, wherein the conditioning agent is as defined in claim 1.
5.TRPM8 receptor modulators are being prepared as the purposes in insect repellent or insecticide composition, wherein the tune Save agent as defined in claim 1.
Purposes of the 6.TRPM8 receptor modulators in the cold sensation of induction packaging, wherein the conditioning agent such as claim 1 is determined Justice.
Purposes of the 7.TRPM8 receptor modulators in the cold sensation of induction textile, wherein the conditioning agent such as claim 1 institute Definition.
8. composition, it includes at least one compound as claimed in claim 1.
9. composition as claimed in claim 8, is selected from：
A) pharmaceutical composition；
B) food；
C) oral care composition；
D) skin care or Haircare composition；
E) insect repellent, insecticide.
10. pharmaceutical composition as claimed in claim 9, it is anti-tumor compositions, bladder disease therapeutic combination or analgesic Composition.
11. food as claimed in claim 9, it is ice cream, mousse, missible oil, beverage or cake.
12. oral care composition as claimed in claim 9, it is toothpaste, mouthwash or chewing gum.
13. skin care as claimed in claim 9 or Haircare composition, it is suncream, sunburn cream, lotion, shampoo or plaster.
14. textile, it uses at least one compound as claimed in claim 1 to arrange.
15. textile as claimed in claim 14, it is shirt, trousers, socks or towel.
16. the packaging material combined with least one compound as claimed in claim 1.
CN201710396933.0A 2008-08-26 2009-08-26 Detection and use of low molecular weight modulators of the cold menthol receptor TRPM8 Active CN107375284B (en)

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